tbuckley/cabot-search huggingface dataset:
P08.04.B The Clinical Frailty Scale is superior to the Karnofsky Performance Status as predictor of overall survival in patients with surgical treatment of brain metastases
Authors: A Krigers, N Pichler, J Kerschbaumer, M Demetz, J Klingenschmid, C Thomé, C F Freyschlag
Journal: Neuro-Oncology (2022)

Abstract Background The Clinical Frailty Scale (CFS) evaluates patients’ level of frailty on a scale from 1 (very fit) to 9 (terminally ill) and is commonly used in geriatric medicine, intensive care and orthopaedics but not in patients harboring neuro-oncological diseases. Our study was conducted to reveal if the usage of CFS generates more reliable prediction of overall survival in patients after brain metastases resection rather than Karnofsky Performance Status (KPS). Material and Methods All patients which were operated for brain metastatic disease at our department from 2005-2019 were included. CFS and KPS were retrospectively assessed for the timepoints pre- and postoperatively as well during follow-up 3-6 months after resection. Results 205 patients with mean follow-up of 22.8 months (CI95% 18.4-27.1) were evaluated. Mean estimated OS was 32.1 months (CI95% 25.0-39.1). CFS showed a median of 3 points (IqR 2-4) at all 3 assessment-points which means patients were “managing well”. Median KPS was 80 preoperative (IqR 80-90) and 90 (IqR 80-100) postoperative as well as on follow-up after 3-6 months. CFS strongly correlated with KPS: preoperatively (r=-0.92; p&amp;lt; 0.001), postoperatively (r=-0.85; p&amp;lt;0.001) and at follow-up (r=-0.93; p&amp;lt;0.001). In the same time, CFS pre- and postoperatively showed only weak correlation with CFS at follow-up after 3-6 months (r=0.30, p&amp;lt;0.001; and r=0.37, p&amp;lt;0.001, correspondingly). In multivariate integrated Cox regression model, the CFS predicted the expected reduction of OS superior to KPS at all 3 assessment-points. One point increase of preoperative CFS represented 30% additional hazard to decease (HR=1.30, CI95% 1.15-1.46; p&amp;lt;0.001), correspondingly postoperative CFS provides 39% (HR=1.39, CI95% 1.25-1.54; p&amp;lt;0.001) and at follow-up 42% of hazard (HR= 1.42, CI95% 1.27-1.59; p&amp;lt;0.001). In case of KPS, decrease of 10 points resulted in additional hazards to decease of 26% (HR=0.974/point, CI95% 0.962-0.987; p&amp;lt;0.001) postoperatively 14% (HR=0.986/point, CI95% 0.978-0.993; p&amp;lt;0.001) and 31% (HR=0.969/point, CI95% 0.959-0.978; p&amp;lt;0.001) at follow-up. Conclusion CFS is a feasible and reliable performance scoring in patients undergoing brain metastasis resection, that provides better OS prediction as compared to KPS. Whereas, CFS at follow-up after 3-6 months specifies the expected OS most accurately. Due to weak correlation between CFS preoperatively vs. postoperatively and in 3-6 months, initial frailty does not predict the patients’ postoperative frailty score.
P04.03.B Rapid DNA methylation-based classification of pediatric brain tumors from ultrasonic aspirate specimens
Authors: M Simon, L P Kuschel, K von Hoff, P Hernáiz Driever, E G Hain, A Koch, D Capper, M Schulz, U Thomale, P Euskirchen
Journal: Neuro-Oncology (2022)

Abstract Background Cavitating ultrasonic aspirator (CUSA) devices are commonly used in neurosurgical procedures to carefully debulk tumor from adjacent healthy brain tissue. Here, we explore the feasibility of using ultrasonic minced tumor tissue to classify otherwise discarded sample material by DNA methylation according to the respective World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) using low pass nanopore whole genome sequencing. Material and Methods 21 ultrasonic aspirated specimens from patients undergoing surgery in the department of pediatric neurosurgery at the Charité-Universitätsmedizin Berlin with either newly diagnosed cerebral lesions or pre-treated lesions were processed by nanopore sequencing to generate copy number profiles and ad-hoc random forest classification. Results were compared to microarray-based routine profiling. Tumor purity was assessed. Results In 19/21 (90.5 %) samples the minimum amount of 1,000 CpG sites were sequenced. In 20/21 (95.2 %) cases copy number variation profiles could be generated and matched microarray derived copy number profiles, allowing for identification of diagnostically or therapeutically relevant pathognomonic alterations. 12/17 (70.6 %) samples were concordantly classified to the corresponding microarray-based diagnosis by routine neuropathological workup. Applying recently defined thresholds for nanopore-based classification resulted in sensitivity of 64.7 % and specificity of 100 %. Conclusion CUSA referred sample material of pediatric brain tumors allows for methylation-based classification according to the respective WHO classification of CNS tumors with acceptable sensitivity and high specificity. Hereby, a promising opportunity for accurate classification of pediatric brain tumors by a time- and cost-efficient advanced molecular technique is offered using otherwise discarded tumor tissue.
P12.14.A The role of onco-metabolite (R2hydroxyglutarate) in the IDH mutant glioblastoma microenvironment
Authors: V M Ravi, S Behringer, K Joseph, J Beck, O Schnell, D H Heiland
Journal: Neuro-Oncology (2022)

Abstract Background Recently, we found that the reactive astrocytes in the IDH wild type glioblastoma contribute to anti-tumor immunity and support pro-oncogenic signaling. Here, we characterized the transcriptomic signature of IDH1/2-mutant glioma associated astrocytes and determined a unique inflammatory transformation, profoundly different to astrocytes in IDH wildtype glioma patients due to an onco-metabolite R-2-hydroxyglutarate using Next generation sequencing and human ex-vivo slice model. Material and Methods We purified and transcriptionally profiled astrocytes from 9 patients with confirmed IDH1-R132H mutation, by means of RNA-sequencing and the data were analyzed using the established pipelines. We also used spatial transcriptomics to evidently show the spatial distribution of astrocytes in IDH-mutated/wildtype glioma samples. We validated our findings using human organotypic slice model inoculated with IDH-mutant cell line or treated with oncometabolite 2-hydroxy glutarate. Additionally, LC-MS was further used to give us a chart of neurotransmitters due to altered microenvironment. Results Our results from RNA sequencing showed a transcriptional transformation of reactive astrocytes within the microenvironment of IDH-mutated tumors compared to wildtype glioma by means of RNA-sequencing of purified astrocytes. And, using our established human neocortical GBM model inoculated with IDH mutant tumor and R-2HG treatment, we showed that we were able to activate inflammatory transcriptional programs in astrocytes, mediated by the presence of microglia. Further, by spatially mapping the transcriptomic profiles of purified microglia, we were able to confirm that microglia also demonstrate inflammatory activation in IDH mutated glioma. This inflammatory astrocyte transformation is associated with a loss of neurotransmitter homeostasis (disrupted levels of glutamate) in the treated sections, as has been previously reported in IDH mutated tumors. Additionally, R-H2G increased neuronal spiking rate in, pointing to potential excitotoxicity. Conclusion Our work provides a crucial contribution towards understanding the role of R-2HG in the IDH mutant glioma microenvironment and sheds light on the significant microenvironmental differences to IDH wild-type glioma.
P02.08.A The relations of focal and total DNA methylation in gliomas
Authors: A Majchrzak-Celińska, M Naskret-Barciszewska, M Giel-Pietraszuk, W Nowak, P Śron, A Barciszewska
Journal: Neuro-Oncology (2022)

Abstract Background The role of epigenetic events in gliomagenesis is undoubtful. However, the role of specific pathological events is not so clear. It was shown that loss in total DNA methylation correlates with higher tumor malignancy and oxidative DNA damage. But promoter methylation of many genes was reported to be significant for gliomas’ malignancy and predictive for the treatment outcome. In carcinogenesis in general global DNA hypomethylation and focal hypermethylation coexist. The aim of our project was to evaluate the correlation between total DNA methylation and promoter methylation of selected genes. Material and Methods We analysed glioma tissues from 60 patients. For total DNA methylation analysis we used the radiolabelling method with TLC separation of nucleotides and content estimation with phosphoimager. For promoter methylation analysis we have chosen: MGMT (O-6-Methylguanine-DNA Methyltransferase), MPG (DNA-3-methyladenine glycosylase), GJA1 (Gap junction alpha-1 protein / connexin 43). The promoter methylation level was evaluated with the methylation-sensitive high-resolution melting (MS-HRM) method. Results Total DNA methylation was reversely correlated with brain tumor grade, confirming that 5-methylcytosine loss is important step in gliomagenesis. From 3 genes only MPG promoter methylation showed clear low reverse correlation with tumor grade. Promoter methylation in GJA1 show low correlation with both, MGMT and MPG, but there was no link between MGMT and MPG. IDHwt presence was significantly correlated with higher tumor grade. Promoter methylations in MPG and GJA1 were better correlated with IDH status than in MGMT. Conclusion There is a clear correlation between total DNA methylation and tumor malignancy. Gene promoter methylation is not highly correlated with total DNA methylation and shows low significance in selected cases. Promoter methylation showed clear correlation with tumor grade only in MPG case. That suggests diverse mechanisms steering DNA methylation in general and local changes. It also shows that total DNA methylation is best predictor of tumor grade.
P18.09.A Single-session stereotactic radiosurgery for large parasellar meningiomas
Authors: R M Emad Eldin, K M Abdel Karim, W A Reda, S R Tawadros, A M Nabil, A M N El Shehaby
Journal: Neuro-Oncology (2022)

Abstract Background The purpose of this study is to assess the long-term efficacy and safety of single-session stereotactic radiosurgery for large (10 cc or more) perioptic intracranial benign meningiomas. Material and Methods In this retrospective study we included 175 patients with large perioptic benign meningiomas (≥ 10 cc) who were treated by single-session SRS. Perioptic meningiomas were defined as meningiomas touching, compressing or within 3 mm of the optic pathway. The median tumor volume was 15 (10-57.3 cc (IQR 8.4 cc)). The median prescription dose was 12 Gy (9-14 Gy (IQR 1 Gy)). Results The median follow up period was 72 months (13-217 months (IQR 65 months)). The tumor control rate was 92%. The PFS at 5- and 10- years was 97% and 80%. Favorable (better/stable) visual outcome was reported in 169 patients (97%) and unfavorable (worse) outcome in 6 patients (3%). Temporary adverse radiation effects were observed in 21 patients (12%) but only 7 (4%) were symptomatic. Sixty-three patients had a blind/non-useful eye according the pre-treatment visual field examination. Visual improvement was observed in blind/non-useful eye in 17 patients (27%) while vision remained unchanged in 46 patients (73%). Ocular nerve palsy improved in 36 patients (61%). Tumor shrinkage was not a prerequisite for cranial nerve improvement. Conclusion Stereotactic radiosurgery provides an effective and safe treatment option for large perioptic meningiomas.
P17.16.B Additional antitumoral activity of TTFields stimulation and Chloride Intracellular Channel 1 inhibition in human glioblastoma primary culture
Authors: M Mazzanti, S Castiglione, C A Mercurio, G Cannavale, I Verduci, F Cianci
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastoma relapse inevitably occurs in the majority of patients after surgery. Chemo- and radiotherapy are in most cases ineffective, while Tumor Treating Fields (TTFields) therapy delays average tumor recurrence by a few months. It is widely accepted that tumor reappearance is a result of the proliferation of residual glioblastoma stem cell (GSC) subpopulation, which escaped surgery. Previous experiments demonstrated that inhibition of the membrane form of Chloride Intracellular Channel 1 (tmCLIC1) is particularly efficient to hit GSCs in glioblastoma human primary cultures. tmCLIC1 is an ideal target as it is express only in the tumor cell membranes. tmCLIC1 blockage slowdown GSC cell cycle at G1/S transition. On the contrary, TTFields act mainly during G2/M progression. The objective of our study is to test the therapeutic potential of combining TTFields exposure with the inhibition of the protein transmembrane Chloride Intracellular Channel 1 (tmCLIC1), which is crucial for GSCs proliferation. Material and Methods Cell preparation: human primary culture from patients’ biopsies. Stimulation device: NOVOCURE Inovitro system®. Stimulation procedure: long-term TTFields stimulation in in-vitro experiments mimics glioblastoma cells’ recrudescence. Analysis: cytofluorimetry for stem cell recognition, cell-cycle progression, and cell count. Results Cell growth is inhibited after the first three days of TTFields exposure. However, despite the chronic presence of TTFields stimulation in prolonged experiments, glioblastoma cells reestablish the ability to proliferate. At the end of twelve days, exponentially growing cells show an increase in stemness markers, a drop in the membrane resistance with a related increase of membrane current, and an average depolarized membrane potential. Twelve days of TTFields treatment resulted in a progressive increase in GSCs in the tumor cell population from 10% to more than 30%. Thus, experiments have been designed to combine TTFields stimulation with tmCLIC1 inhibition. This would include in the treatment of the vast majority of the glioblastoma cell population. After twelve days, the parallel antiproliferative activities show a complete impairment in cell proliferation. Conclusion The additive effect of TTFields stimulation and tmCLIC1 ion channel inhibition could represent an efficacious step forward to optimize an antitumoral therapy against glioblastoma expansion.
P14.04.A Tracking<i>TERT</i>promoter and<i>IDH1</i>mutations in liquid biopsies - suitable biomarkers for disease monitoring in glioma patients?
Authors: K Bruckner, S Madlener, A Lang, B Kiesel, J Furtner-Srajer, J Hainfellner, C Haberler, S Spiegl-Kreinecker, C Dorfer, I Slavc, J Gojo, K Rössler, D Lötsch-Gojo
Journal: Neuro-Oncology (2022)

Abstract Background Mutations within the telomerase reverse transcriptase promoter (TERTprom) and isocitrate dehydrogenase (IDH) account for the most common genetic alterations in gliomas. Each of these mutations impact clinicopathologic diagnosis and course of diseases. While TERTprom mutations are frequently detected in glioblastoma, IHD mutations are assigned to astrocytoma of grade 2-4, thus mostly associated with better prognosis. In the era of precision oncology, molecular profiling and continuous monitoring of treatment response or relapse are of increasing importance. Accordingly, this study aims to detect TERTprom and IDH mutations in plasma-derived cell-free (cf)DNA of gliomas. The mutant allele frequencies (MAF) will be compared retrospectively to clinico-pathological parameters including extent of resection and tumor progression. Material and Methods Digital droplet PCR (ddPCR) analyses were performed using the QX200TM Digital Droplet System from BioRad. First, to evaluate probes for ddPCR, genomic DNA of several brain tumor cell models (n=6) and tumor tissue (n=1), as well as cfDNA of plasma (n=3) from samples with known TERTprom and IDH mutation status was investigated. For detection of IDH mutations, the unique assay ID dHSaMDV2010055 (IDH1p.R132H) and for TERTprom mutations the TaqMan dPCR Liquid Biopsy Assays for C228T (Hs000000092) and C250T (Hs000000093) were used. The results of ddPCR were analyzed with QuantaSoftTM software and the MAF was calculated Results To validate the detection method for IDH1R132H, we analyzed the MAF in one tissue and corresponding plasma sample of a confirmed IDH1-mutated astrocytoma. In addition, plasma from one astrocytoma grade 2-3 as well as from an IDH1-mutated glioblastoma was tested. Interestingly, both astrocytoma cases exhibited undetectable or very low MAF ranging from 0.1 to 1% in tissue as well as in plasma samples, while in plasma from the high-grade glioblastoma case, IDH1R132H was detected with a frequency of 1.9%. Due to the high GC content of the TERT promoter region, amplification steps are challenging. Accordingly, we first optimized ddPCR conditions for C228T and C250T probes by adding 7-deaza-2-deoxyguanosine-5-triphosphate (7-ddGTP) in varying concentrations to each ddPCR reaction. When using 4µM of 7-ddGTP per sample, a clear separation between mutant and wild-type droplets was reached, detecting MAF between 36-63% in DNA from cell culture models. Conclusion Within this pilot study we optimized the ddPCR method for the detection of IDH1R132H and TERTprom mutations in plasma and tissue samples. Subsequently, we hypothesize that these mutations are suitable liquid biomarkers correlating with extent of resection and tumor progression in gliomas.
P11.56.A Shared and personalized decision-making in pre-surgical consultations of brain tumor patients and neurosurgeons
Authors: I J M Bras, M M Sitskoorn, I J M van Vugt, M C W Joosen, A P Y Hoogendoorn, G J Rutten, K Gehring
Journal: Neuro-Oncology (2022)

Abstract Background In order to assess whether the oncological benefits outweigh the functional risks of treatment for an individual patient, it is important that physicians involve patients in decision-making and personalize the process. This is especially important for brain tumor patients considering the limited treatment options available. The aim of this study is to evaluate shared decision-making and the personalization of the decision-making process during consultations of brain tumor patients and their neurosurgeons. Material and Methods For this observational study we collected 66 audio-recordings of pre-surgical consultations of adult brain tumor patients (glioma, meningioma) and their neurosurgeons. A preliminary analysis based on a shared decision-making template was conducted on 14/66 transcribed audio-recordings to assess in how many consultations the following key elements of shared decision-making were present, namely 1) offering a choice to the patient and emphasizing that the patient’s perspective is important in making the decision, 2) discussing treatment options with benefits and risks and 3) asking about treatment preferences and personal goals. Next, thematic analysis will be performed by two independent researchers until data saturation is reached to gain insight into personalization of the decision-making process as an integral part of shared decision-making. Results Preliminary findings show that 1) offering the patient a choice and emphasizing that the perspective of the patient is important in decisions was done in 12/14 consultations; 2) discussing treatment options with benefits and risks was present in every consultation (14/14); and 3) in 12/14 consultations the neurosurgeon asked the patient about his or her treatment preference. However, explicitly asking the patient about personal goals occurred only in 3/14 consultations. By the time of the conference, we expect to have explored the decision-making process more in-depth and will be able to share the themes we have identified related to personalization of the decision-making process. Conclusion Key elements of shared decision-making were present in most pre-surgical consultations, except for asking patients about their personal goals. Discussing personal goals that patients have concerning daily life may facilitate personalization of the decision-making process.
P10.19.B An immunotoxin targeting CD317 for the treatment of glioblastoma
Authors: D Gramatzki, T Weiss, L Hänsch, M Silginer, E J Rushing, P Roth, M Gramatzki, M Peipp, M Weller
Journal: Neuro-Oncology (2022)

Abstract Background CD317 is an interferon-inducible cell surface receptor expressed in several solid cancer types. HM1.24-ETA’ is a small immunotoxin with a CD317 single-chain variable fragment (svFv) antibody fused to a truncated version of Pseudomonas aeruginosa exotoxin A (ETA’) that is explored as a novel therapeutic approach in CD317-expressing tumors. Material and Methods CD317 mRNA expression in human gliomas and its association with survival was analyzed using the database of the Cancer Genome Atlas (TCGA). CD317 protein levels in human gliomas were assessed by immunohistochemistry. CD317 mRNA expression was assessed by RT-PCR and CD317 protein levels by flow cytometry in 13 human glioma cell lines in vitro. Efficacy of HM1.24-ETA’ was analyzed in acute cytotoxicity assays in vitro. Finally, HM1.24-ETA’ was evaluated in the intracranial human LN-229 glioma xenograft nude mouse model after intravenous injection. Results Interrogation of the TCGA database showed that increased CD317 mRNA expression correlated with grade of malignancy among isocitrate dehydrogenase (IDH) wildtype and IDH-mutant gliomas. Enhanced CD317 mRNA expression was associated with inferior survival in glioblastoma and astrocytoma, IDH-mutant, WHO grade 4. Immunohistochemistry confirmed CD317 overexpression in human glioblastoma compared to lower grade astrocytomas. CD317 was expressed heterogeneously on mRNA and protein levels in glioma cell lines in vitro. HM1.24-ETA’ induced acute cytotoxicity in CD317-positive glioma cells in vitro. CD317 expression and susceptibility to HM1.24-ETA’-induced cell death were enhanced by interferon-β. HM1.24-ETA’ prolonged survival in the LN-229 xenograft nude mouse model. Conclusion These data define CD317 as a novel target for treatment of human gliomas with immunoconjugates.